Britta Siegmund

Charité Universitätsmedizin Berlin, Berlín, Berlin, Germany

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Publications (188)818.98 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Macrophages are key players in inflammatory bowel diseases (IBD). This study aimed to determine site-specific effects of defined macrophage subtypes on the integrity of the intestinal epithelial barrier. Macrophage subtypes in situ in intestinal specimens of patients with IBD were visualized by immunohistochemistry. In vitro polarization of human peripheral CD14 cells yielded M1 or M2 macrophages. The influence of primary monocytes or macrophage subtypes on epithelial barrier integrity was analyzed by transepithelial resistance measurements, Western blot analysis, confocal laser scanning microscopy, and cytometric bead array in a coculture model of primary human macrophages and layers of intestinal epithelial cell lines. The lamina propria of the inflamed intestine in patients with IBD, predominantly in Crohn's disease, is massively infiltrated by CD68 cells also positive for inducible nitric oxide synthase and tumor necrosis factor (TNF) α. The presence of M1 macrophage shifted the balance in the local macrophage compartment towards a proinflammatory state. In the coculture model, monocytes and M1 macrophages reduced transepithelial resistance as a marker for epithelial barrier integrity. The mechanisms for paracellular leakage included intracellular relocalization of tight junction proteins like claudin-2 and epithelial cell apoptosis. Determined by specific cytokine blockade, M1 macrophages exerted their deleterious effect mainly through TNF-α, whereas monocyte-mediated damage was driven by the inflammasome effector cytokines, interleukin-1β and interleukin-18. Lamina propria monocytes and M1 macrophages invading intestinal tissues directly contribute to disrupting the epithelial barrier through deregulation of tight junction proteins and induction of epithelial cell apoptosis, thus driving intestinal inflammation in IBD.
    Inflammatory Bowel Diseases 04/2015; DOI:10.1097/MIB.0000000000000384 · 5.48 Impact Factor
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    ABSTRACT: Inflammatory bowel disease (IBD)-like conditions in glycogen storage disease (GSD) type Ib have been predominantly described in children. Signs and symptoms of GSD type Ib are hypoglycemia, pancytopenia and hepatosplenomegaly. Based on few published cases, there is evidence that granulocyte-colony stimulating factor (G-CSF) in patients with glycogenosis-related pancytopenia might ameliorate the IBD-like disease through leukocyte increase. Here we firstly describe a case of an adult 33-year-old Caucasian male patient with GSD type Ib accompanied with IBD-like disease with persistent pancytopenia despite moderate-dose G-CSF treatment. Recent vomiting and abdominal discomfort were due to a high-grade stenosis in the transverse colon. A dose increase of the G-CSF successfully normalized his leukocyte count. However, the stenosis worsened and surgical therapy was needed. We suggest that symptomatic patients with GSD type Ib should undergo endoscopic examination in order to detect IBD-like disease and to initiate early treatment.
    BMC Gastroenterology 04/2015; 15(1):45. DOI:10.1186/s12876-015-0271-9 · 2.11 Impact Factor
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    ABSTRACT: IL-17-producing Th17 cells mediate immune responses against a variety of fungal and bacterial infections. Signaling via NF-κB has been linked to the development and maintenance of Th17 cells. We analyzed the role of the unusual inhibitor of NF-κB, IκBNS, in the proliferation and effector cytokine production of murine Th17 cells. Our study demonstrates that nuclear IκBNS is crucial for murine Th17 cell generation. IκBNS is highly expressed in Th17 cells; in the absence of IκBNS, the frequencies of IL-17A-producing cells are drastically reduced. This was measured in vitro under Th17-polarizing conditions and confirmed in two colitis models. Mechanistically, murine IκBNS (-/-) Th17 cells were less proliferative and expressed markedly reduced levels of IL-2, IL-10, MIP-1α, and GM-CSF. Citrobacter rodentium was used as a Th17-inducing infection model, in which IκBNS (-/-) mice displayed an increased bacterial burden and diminished tissue damage. These results demonstrate the important function of Th17 cells in pathogen clearance, as well as in inflammation-associated pathology. We identified IκBNS to be crucial for the generation and function of murine Th17 cells upon inflammation and infection. Our findings may have implications for the therapy of autoimmune conditions, such as inflammatory bowel disease, and for the treatment of gut-tropic infections. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 02/2015; DOI:10.4049/jimmunol.1401964 · 5.36 Impact Factor
  • Zeitschrift für Gastroenterologie 02/2015; 53(02):136-136. DOI:10.1055/s-0034-1397525 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 02/2015; 53(2):136. · 1.67 Impact Factor
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    ABSTRACT: The cell adhesion molecule CD2 facilitates antigen-independent T-cell activation and CD2 deficiency or blockade reduces intestinal inflammation in murine models. We here aimed to evaluate the therapeutic potential of monoclonal antibodies (mAb) specific for human CD2 in colitis treatment. Transfer colitis induced by naϊve CD4+ T cells expressing human CD2 was treated with anti-human CD2 mAb. The mAb CB.219 protected from severe colitis in a preventive treatment regimen, while therapeutic treatment ameliorated intestinal inflammation. Diminished intestinal tissue damage was paralleled by a profound suppression of lamina propria lymphocytes to produce proinflammatory cytokines and tumor necrosis factor α as well as the neutrophil chemoattractant CXC motif ligand 1 and the CC chemokine ligand 3. Furthermore, infiltration with macrophages and T cells was low. Thus, reduced intestinal inflammation in our humanized colitis model by targeting CD2 on T cells with the mAb CB.219 suggests a novel approach for colitis treatment.
    Clinical Immunology 01/2015; 157(1). DOI:10.1016/j.clim.2015.01.004 · 3.99 Impact Factor
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    ABSTRACT: Thiopurines (azathioprine and 6-mercaptopurine) are the most frequently used drugs in the treatment of patients with Crohn's disease. In current guidelines published by the German Society of Gastroenterology, Nutritional and Metabolic Diseases (DGVS) in 2014 and by the European Crohn´s and Colitis Organisation (ECCO) in 2010 different indications have been suggested. However, efficacy of azathioprine has been substantially questioned by recent publications in adults as well as in children examining the efficacy of early initiation of this treatment. These articles were published after release of the aforementioned guidelines. Therefore, in this survey recently published data are discussed on the background of our knowledge on the efficacy of azathioprine and 6-mercaptopurine developed in many years, and suggestions for the future use of these substances in the treatment of patients with Crohn's disease will be provided. © Georg Thieme Verlag KG Stuttgart · New York.
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  • Uta Syrbe, Britta Siegmund
    Gut 11/2014; DOI:10.1136/gutjnl-2014-308436 · 13.32 Impact Factor
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    Lea I Kredel, Britta Siegmund
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    ABSTRACT: Obesity has become one of the main threats to health worldwide and therefore gained increasing clinical and economic significance as well as scientific attention. General adipose-tissue accumulation in obesity is associated with systemically increased pro-inflammatory mediators and humoral and cellular changes within this compartment. These adipose-tissue changes and their systemic consequences led to the concept of obesity as a chronic inflammatory state. A pathognomonic feature of Crohn's disease (CD) is creeping fat (CF), a locally restricted hyperplasia of the mesenteric fat adjacent to the inflamed segments of the intestine. The precise role of this adipose-tissue and its mediators remains controversial, and ongoing work will have to define whether this compartment is protecting from or contributing to disease activity. This review aims to outline specific cellular changes within the adipose-tissue, occurring in either obesity or CF. Hence the potential impact of adipocytes and resident immune cells from the innate and adaptive immune system will be discussed for both diseases. The second part focuses on the impact of generalized adipose-tissue accumulation in obesity, respectively on the locally restricted form in CD, on intestinal inflammation and on the closely related integrity of the mucosal barrier.
    Frontiers in Immunology 09/2014; 5:462. DOI:10.3389/fimmu.2014.00462
  • LeaI Kredel, Arvind Batra, Britta Siegmund
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    ABSTRACT: Purpose of review This review summarizes current knowledge on the contribution of mesenteric adipose tissue in intestinal inflammation. We will describe the cellular and humoral characteristics of creeping fat, their potential impact for Crohn's disease and propose a working model for the critical interplay between the creeping fat and the inflamed intestine. Recent findings Creeping fat can be distinguished from healthy adipose tissue by its distinctively small adipocytes, by a specific microenvironment defined by high levels of adipokines and by a dominant immune cell infiltration. In Crohn's disease transmural inflammation facilitates increased bacterial translocation into the creeping fat. Trans localizing antigens can directly activate (pre)adipocytes via innate receptors. Adipocyte-derived mediators modulate phenotype and function of innate and adaptive immune cells. Activated (pre)adipocytes and adipokine-modulated immune cells might support a degree of inflammatory activation within the creeping fat that allows competent immune defense against exogenous factors while preventing systemic inflammation. Summary Fat tissue as an active organ in health and disease has been ignored for too long. The last few years of research provided evidence for the complex metabolic and immunological functions of adipose tissue. On the basis of the available data, creeping fat in Crohn's disease exerts a protective function by a localized anti-inflammatory effect, thus preventing a systemic inflammatory response.
    Current Opinion in Gastroenterology 09/2014; 30(6). DOI:10.1097/MOG.0000000000000116 · 3.66 Impact Factor
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    ABSTRACT: Early enteral nutrition is recommended for patients in intensive care units, but nutrition provision is often hindered by a variety of unit-specific problems.
    American Journal of Critical Care 09/2014; 23(5):396-403. DOI:10.4037/ajcc2014140 · 1.60 Impact Factor
  • J Maul, B Siegmund
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    ABSTRACT: Chronic inflammatory bowel diseases are mainly represented by Crohn's disease and ulcerative colitis. Current epidemiological data indicate a rise in incidence over the last five decades in the Western world. Consequently resulting not only in the reconsideration of the pathogenesis of inflammatory bowel diseases but furthermore emphasizing the need for a curative approach. With this review we aim to provide a concise overview on pathogenesis, diagnostics as well as therapy with a particular focus on medical strategies after ileocecal resection in Crohn's disease. In the end the near future with regard to therapeutic strategies to be introduced into daily clinical work will be described.
    DMW - Deutsche Medizinische Wochenschrift 09/2014; 139(36):1771-1775. DOI:10.1055/s-0034-1370229 · 0.55 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386043 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386016 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386039 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386057 · 1.67 Impact Factor
  • LI Kredel, A Kühl, B Siegmund
    Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386044 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 08/2014; 52(08). DOI:10.1055/s-0034-1386038 · 1.67 Impact Factor
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    ABSTRACT: Histomorphology remains a powerful routine evaluating intestinal inflammation in animal models. Emphasizing the focus of a given animal study, histopathology can overstate differences between established models. We aimed to systematize histopathological evaluation of intestinal inflammation in mouse models facilitating interstudy comparisons. Samples of all parts of the intestinal tract from well-established mouse models of intestinal inflammation were evaluated from hematoxylin/eosin-stained sections and specific observations confirmed by subsequent immunohistochemistry. Three main categories sufficiently reflected the severity of histopathology independent of the localization and the overall extent of an inflammation: (i) quality and dimension of inflammatory cell infiltrates, (ii) epithelial changes and (iii) overall mucosal architecture. Scoring schemata were defined along specified criteria for each of the three categories. The direction of the initial hit proved crucial for the comparability of histological changes. Chemical noxes, infection with intestinal parasites or other models where the barrier was disturbed from outside, the luminal side, showed high levels of similarity and distinct differences to changes in the intestinal balance resulting from inside events like altered cytokine responses or disruption of the immune cell homeostasis. With a high degree of generalisation and maximum scores from 4-8 suitable scoring schemata accounted specific histopathological hallmarks. Truly integrating demands and experiences of gastroenterologists, mouse researchers, microbiologists and pathologists we provide an easy-to-use guideline evaluating histomorphology in mouse models of intestinal inflammation. Standard criteria and definitions facilitate classification and rating of new relevant models, allow comparison in animal studies and transfer of functional findings to comparable histopathologies in human disease.
    International journal of clinical and experimental pathology 08/2014; 7(8):4557-4576. · 1.78 Impact Factor

Publication Stats

3k Citations
818.98 Total Impact Points

Institutions

  • 2004–2015
    • Charité Universitätsmedizin Berlin
      • • Medical Department, Division of Hepatology and Gastroenterology
      • • Institute of Health Sciences Education and Nursing Science
      • • Department of Gastroenterology, Infectiology and Rheumatology
      • • Institute of Medical Informatics
      Berlín, Berlin, Germany
    • Mental Health Center of Denver
      Denver, Colorado, United States
  • 2008
    • St. Marien- und St. Annastiftskrankenhaus
      Ludwigshafen, Rheinland-Pfalz, Germany
  • 2006–2008
    • University of Colorado
      • • Division of Infectious Diseases
      • • Department of Medicine
      Denver, Colorado, United States
  • 2005
    • University Hospital of Lausanne
      • Institut universitaire de pathologie
      Lausanne, VD, Switzerland
  • 2003–2004
    • Johannes Gutenberg-Universität Mainz
      Mayence, Rheinland-Pfalz, Germany
    • Freie Universität Berlin
      Berlín, Berlin, Germany
  • 1997–2001
    • Ludwig-Maximilian-University of Munich
      • • Department of Clinical Pharmacology
      • • Department of Internal Medicine II
      München, Bavaria, Germany